Fentanyl is a synthetic m-opioid receptor agonist with high lipid solubility. Fentanyl is generic name given to the chemical compound N-(1-phenethyl-4-piperidyl)propionanilide. It is well known narcotic analgesic used for both general as well as regional anesthesia and both during and or after surgery. It is 30 to 100 times more powerful than morphine and shows less emetic activity than morphine. Fentanyl citrate was first used as an intravenous anesthetic under the name ‘Sublimaze’ in 1960. It is also mydritic and cholinergic in its action and found useful as analgesic particularly treating cancer pain. It has an analgesic potency 1000 times that of morphine. It has more than 12 different analogs.
Fentanyl was first synthesized in 1960 by Paul Janssen founder of Janssen Pharmaceutica involving reacting N-phenethylpiperidone with aniline to produce 4-anilino-N-phenethylpiperidone with yield of about 50-80% using sodium borohydride at room temperature followed by reacting with propionyl chloride in presence of pyridine wherein the reaction is exothermic and thus requires stringent process conditions. The fentanyl thus obtained with a yield over 90% is further purified by crystallization.
U.S. Pat. No. 3,164,600 ('600) dated Jan. 5, 1965 to Janssen in column 2 lines 45 to 70 and column 3, (Examples), discloses a process for the preparation of fentanyl that involves following five steps:                (i) refluxing mixture of 1-benzyl-4-piperidone, aniline, toluene and 4 toluenesulfonic acid for 15 hrs to produce N-(1-benzyl-4-piperydylidene)aniline,        (ii) reducing N-(1-benzyl-4-piperydylidene)aniline so obtained using lithium aluminium hydride in anhydrous ether to 1-benzyl-4-anilinopiperidine in nitrogen atmosphere, then        (iii) alkalizing by refluxing with propionic anhydride for 7 hrs to give N-(1-benzyl-4-piperydylidene)propionanilide,        (iv) subjecting to debenzylation by employing hydrogenation over palladium on charcoal catalyst in ethanol to get N-(4-piperydyl)propionanilide, and finally        (v) treating a mixture of N-(4-piperydyl)propionanilide, sodium carbonate and potassium iodide in hexone with the solution of β phenethylchloride in 4-methyl-2-pentanone and refluxed for 27 hrs to obtain fentanyl [N-(1-phenethyl-4-piperidyl)propionanilide].        
The main disadvantage associated with this process is a multi-step, hence requires more time and over all appreciably reduced yield.
The other drawback is that it requires stringent operating conditions such as reflux temperature in all five steps thus making the process energy extensive, which in turn makes the process uneconomical.
The other drawback is that every process step makes use of organic solvent requiring removal of these solvents, which not only adds to the overall cost of the process but also makes the process environmentally unsound and unsafe.
Further steps (i), (ii), (iii), & (v) being moisture sensitive requires additional infrastructure and precautions, which is undesirable for large scale production.
Lithium aluminium hydride in step (ii) reacts violently with water and liberates hydrogen, which is likely to cause the material ignite. Thus, for large scale production, use of lithium aluminium hydride in step (ii) is undesirable from safety and environmental point of view.
Additionally, the diethyl ether used is highly inflammable low boiling organic solvent posing fire hazards that requires special fire safety measures particularly in up scaling of the process.
Similarly the palladium charcoal used in hydrogenation/debenzylation increases the cost of the process.
Further, the effluent stream of the subject process is likely to impair the environment.
In general, the process as disclosed in '600 is energy extensive, cost extensive, time consuming, requires sophisticated infrastructure to maintain stringent operating conditions, requires specially trained skilled personnel, likely to impair ecosystem & environment and unfit for large scale production, i.e., industrially and commercially unviable.
Polish patent No. 72,416 describes a process for the preparation of fentanyl also comprises of following five steps:                (i) condensation of 2-phenylethylamine with methyl or ethyl acrylate to get N,N-bis(2carbalkoxyethyl)-phenylethylamine,        (ii) cyclising the said amine in presence of sodium methoxide (alkoxide) to give 1-(2-phenylethyl)piperidine-4-one,        (iii) condensing the said 1-(2-phenylethyl)piperidine-4-one with aniline to give 1-(2-phenylethyl)piperidinylidene aniline, followed by        (iv) reducing by employing lithium aluminium hydride and subsequently        (v) acylating to procure fentanyl.        
One of the main drawbacks associated with this process is employing moisture sensitive sodium methoxide and lithium aluminium hydride, the threats of which are described herein before.
Further, this process also involves five steps and thus inherits the draw backs associated therewith.
In general, this process is also cost extensive, unsafe to environment, requires special operational conditions and thus unfeasible for industrial and commercial applications.
The Indian application No. 2554/DEL/2004 to DRDO discloses a method comprising: (i) refluxing 4-piperidonehydrochloride monohydrate with phenethyl bromide in acetonitrile in presence of potassium carbonate and Tetra butyl Ammonium Bromide (TABA) to give NPP (N-phenethyl-4-piperidone) (II) reacting NPP with aniline in presence of zinc and carboxylic acid preferably acetic acid to give ANPP, then reacting with propionyl chloride to get fentanyl. This process claims advantage over the prior art in (a) reducing number of steps from five to 3, (b) employing all readily available indigenously available reactants, and (c) eliminating employing moisture sensitive (sodium methoxide), fire hazard reagents (lithium metal hydride) and highly flammable low boiling solvent.
Though the process disclosed in the application is obviating drawbacks of the existing process to some extent, it suffers from the following drawbacks:                The process is low yielding,        Polymerization of 4-piperidone hydrochloride monohydrate reactant takes place in step (i), which results in increased load on effluent,        Using organic solvent as a reaction medium and removal of organic solvent is necessary; this adds to the cost as well as makes the process environmentally unsafe/unsound.        Requirement of anhydrous conditions.        
In view of this there is a need to provide simple, high yielding, cost effective, eco-friendly, environmentally safe, sound and beneficial, industrially feasible, that does not require stringent process conditions, sophisticated infrastructure and especially skilled personnel.